Abstract
Neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS) and prion diseases are increasingly being realized to have common cellular and molecular mechanisms including protein aggregation and inclusion body formation. The aggregates usually consist of fibers containing misfolded protein with a β-sheet conformation, termed amyloid. There is partial but not perfect overlap among the cells in which abnormal proteins are deposited and the cells that degenerate. The most likely explanation is that inclusions and other visible protein aggregates represent an end stage of a molecular cascade of several steps, and that earlier steps in the cascade may be more directly tied to pathogenesis than the inclusions themselves. For several diseases, genetic variants assist in explaining the pathogenesis of the more common sporadic forms and developing mouse and other models. There is now increased understanding of the pathways involved in protein aggregation, and some recent clues have emerged as to the molecular mechanisms of cellular toxicity. These are leading to approaches toward rational therapeutics.
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References
Taylor, J.P., Hardy, J. & Fischbeck, K.H. Toxic proteins in neurodegenerative disease. Science 296, 1991–1995 (2002).
Bates, G. Huntingtin aggregation and toxicity in Huntington's disease. Lancet 361, 1642–1644 (2003).
Caughey, B. & Lansbury, P.T. Protofibrils, pores, fibrils, and neurodegeneration: separating the responsible protein aggregates from the innocent bystanders. Annu. Rev. Neurosci. 26, 267–298 (2003).
Berke, S.J. & Paulson, H.L. Protein aggregation and the ubiquitin proteasome pathway: gaining the UPPer hand on neurodegeneration. Curr. Opin. Genet. Dev. 13, 253–261 (2003).
Ross, C.A. & Pickart, C. The ubiquitin-proteasome pathway in Parkinson's and other neurodegenerative diseases. Trends Cell Biol. (2004).
Nussbaum, R.L. & Ellis, C.E. Alzheimer's disease and Parkinson's disease. N. Engl. J. Med. 348, 1356–1364 (2003).
Wong, P.C., Cai, H., Borchelt, D.R. & Price, D.L. Genetically engineered mouse models of neurodegenerative diseases. Nat. Neurosci. 5, 633–639 (2002).
Ross, C.A. When more is less: pathogenesis of glutamine repeat neurodegenerative diseases. Neuron 15, 493–496 (1995).
Selkoe, D.J. Folding proteins in fatal ways. Nature 426, 900–904 (2003).
Davies, S.W. et al. Formation of neuronal intranuclear inclusions underlies the neurological dysfunction in mice transgenic for the HD mutation. Cell 90, 537–548 (1997).
Scherzinger, E. et al. Self-assembly of polyglutamine-containing huntingtin fragments into amyloid-like fibrils: implications for Huntington's disease pathology. Proc. Natl. Acad. Sci. USA 96, 4604–4609 (1999).
Vonsattel, J.P. et al. Neuropathological classification of Huntington's disease. J. Neuropathol. Exp. Neurol. 44, 559–577 (1985).
Kuemmerle, S. et al. Huntington aggregates may not predict neuronal death in Huntington's disease. Ann. Neurol. 46, 842–849 (1999).
Gutekunst, C.A. et al. Nuclear and neuropil aggregates in Huntington's disease: relationship to neuropathology. J. Neurosci. 19, 2522–2534 (1999).
Becher, M.W. et al. Intranuclear neuronal inclusions in Huntington's disease and dentatorubral and pallidoluysian atrophy: correlation between the density of inclusions and IT15 CAG triplet repeat length. Neurobiol. Dis. 4, 387–397 (1998).
Myers, R.H. et al. Clinical and neuropathologic assessment of severity in Huntington disease. Neurology 38, 341–347 (1988).
Venkatraman, P., Wetzel, R., Tanaka, M., Nukina, N. & Goldberg, A.L. Eukaryotic proteasomes cannot digest polyglutamine sequences and release them during degradation of polyglutamine-containing proteins. Mol. Cell 14, 95–104 (2004).
Huang, C.C. et al. Amyloid formation by mutant huntingtin: threshold, progressivity and recruitment of normal polyglutamine proteins. Somat. Cell Mol. Genet. 24, 217–233 (1998).
Kazantsev, A., Preisinger, E., Dranovsky, A., Goldgaber, D. & Housman, D. Insoluble detergent-resistant aggregates form between pathological and nonpathological lengths of polyglutamine in mammalian cells. Proc. Natl. Acad. Sci. USA 96, 11404–11409 (1999).
Margolis, R.L. & Ross, C.A. Expansion explosion: new clues to the pathogenesis of repeat expansion neurodegenerative diseases. Trends Mol. Med. 7, 479–482 (2001).
Orr, H.T. & Zoghbi, H.Y. SCA1 molecular genetics: a history of a 13 year collaboration against glutamines. Hum. Mol. Genet. 10, 2307–2311 (2001).
Sen, S., Dash, D., Pasha, S. & Brahmachari, S.K. Role of histidine interruption in mitigating the pathological effects of long polyglutamine stretches in SCA1: a molecular approach. Protein Sci. 12, 953–962 (2003).
Selkoe, D.J. Alzheimer's disease is a synaptic failure. Science 298, 789–791 (2002).
Hardy, J. & Selkoe, D.J. The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science 297, 353–356 (2002).
Serpell, L.C. & Smith, J.M. Direct visualisation of the β-sheet structure of synthetic Alzheimer's amyloid. J. Mol. Biol. 299, 225–231 (2000).
Esler, W.P. & Wolfe, M.S. A portrait of Alzheimer secretases—new features and familiar faces. Science 293, 1449–1454 (2001).
Citron, M. Alzheimer's disease: treatments in discovery and development. Nat. Neurosci. 5 (suppl.), 1055–1057 (2002).
Goedert, M. Tau protein and neurodegeneration. Semin. Cell Dev. Biol. 15, 45–49 (2004).
Ingram, E.M. & Spillantini, M.G. Tau gene mutations: dissecting the pathogenesis of FTDP–17. Trends Mol. Med. 8, 555–562 (2002).
Forno, L.S. Neuropathology of Parkinson's disease. J. Neuropathol. Exp. Neurol. 55, 259–272 (1996).
Dawson, T.M. & Dawson, V.L. Rare genetic mutations shed light on the pathogenesis of Parkinson disease. J. Clin. Invest 111, 145–151 (2003).
Valente, E.M. et al. Hereditary early-onset Parkinson's disease caused by mutations in PINK1. Science 304, 1158–1160 (2004).
Cleveland, D.W. & Rothstein, J.D. From Charcot to Lou Gehrig: deciphering selective motor neuron death in ALS. Nat. Rev. Neurosci. 2, 806–819 (2001).
Bruijn, L.I. et al. Aggregation and motor neuron toxicity of an ALS-linked SOD1 mutant independent from wild-type SOD1. Science 281, 1851–1854 (1998).
Rakhit, R. et al. Oxidation-induced misfolding and aggregation of superoxide dismutase and its implications for amyotrophic lateral sclerosis. J. Biol. Chem. 277, 47551–47556 (2002).
Prusiner, S.B. Shattuck lecture—neurodegenerative diseases and prions. N. Engl. J. Med. 344, 1516–1526 (2001).
Lindquist, S., Krobitsch, S., Li, L. & Sondheimer, N. Investigating protein conformation-based inheritance and disease in yeast. Phil. Trans. R. Soc. Lond. B 356, 169–176 (2001).
Scheibel, T., Bloom, J. & Lindquist, S.L. The elongation of yeast prion fibers involves separable steps of association and conversion. Proc. Natl. Acad. Sci. USA 101, 2287–2292 (2004).
Ma, J., Wollmann, R. & Lindquist, S. Neurotoxicity and neurodegeneration when PrP accumulates in the cytosol. Science 298, 1781–1785 (2002).
Ma, J. & Lindquist, S. Conversion of PrP to a self-perpetuating PrPSc-like conformation in the cytosol. Science 298, 1785–1788 (2002).
Eanes, E.D. & Glenner, G.G. X-ray diffraction studies on amyloid filaments. J. Histochem. Cytochem. 16, 673–677 (1968).
Sunde, M. & Blake, C.C. From the globular to the fibrous state: protein structure and structural conversion in amyloid formation. Q. Rev. Biophys. 31, 1–39 (1998).
Benzinger, T.L. et al. Propagating structure of Alzheimer's β-amyloid(10–35) is parallel β-sheet with residues in exact register. Proc. Natl. Acad. Sci. USA 95, 13407–13412 (1998).
Tycko, R. Insights into the amyloid folding problem from solid-state NMR. Biochemistry 42, 3151–3159 (2003).
Torok, M. et al. Structural and dynamic features of Alzheimer's Aβ peptide in amyloid fibrils studied by site-directed spin labeling. J. Biol. Chem. 277, 40810–40815 (2002).
Der-Sarkissian, A., Jao, C.C., Chen, J. & Langen, R. Structural organization of α-synuclein fibrils studied by site-directed spin labeling. J. Biol. Chem. 278, 37530–37535 (2003).
Benzinger, T.L. et al. Two-dimensional structure of β-amyloid(10–35) fibrils. Biochemistry 39, 3491–3499 (2000).
Balbach, J.J. et al. Amyloid fibril formation by Aβ16–22, a seven-residue fragment of the Alzheimer's β-amyloid peptide, and structural characterization by solid state NMR. Biochemistry 39, 13748–13759 (2000).
Williams, A.D. et al. Mapping Aβ amyloid fibril secondary structure using scanning proline mutagenesis. J. Mol. Biol. 335, 833–842 (2004).
Thakur, A.K. & Wetzel, R. Mutational analysis of the structural organization of polyglutamine aggregates. Proc. Natl. Acad. Sci. USA 99, 17014–17019 (2002).
Ross, C.A., Poirier, M.A., Wanker, E.E. & Amzel, M. Polyglutamine fibrillogenesis: the pathway unfolds. Proc. Natl. Acad. Sci. USA 100, 1–3 (2003).
Chen, S., Berthelier, V., Hamilton, J.B., O'Nuallain, B. & Wetzel, R. Amyloid-like features of polyglutamine aggregates and their assembly kinetics. Biochemistry 41, 7391–7399 (2002).
O'Nuallain, B. & Wetzel, R. Conformational Abs recognizing a generic amyloid fibril epitope. Proc. Natl. Acad. Sci. USA 99, 1485–1490 (2002).
Uversky, V.N. Protein folding revisited. A polypeptide chain at the folding-misfolding-nonfolding cross-roads: which way to go? Cell Mol. Life Sci. 60, 1852–1871 (2003).
Clarke, G. et al. A one-hit model of cell death in inherited neuronal degenerations. Nature 406, 195–199 (2000).
Dobson, C.M. Principles of protein folding, misfolding and aggregation. Semin. Cell Dev. Biol. 15, 3–16 (2004).
Sacchettini, J.C. & Kelly, J.W. Therapeutic strategies for human amyloid diseases. Nat. Rev. Drug Discov. 1, 267–275 (2002).
Lansbury, P.T., Jr. Structural neurology: are seeds at the root of neuronal degeneration? Neuron 19, 1151–1154 (1997).
Soto, C. Unfolding the role of protein misfolding in neurodegenerative diseases. Nat. Rev. Neurosci. 4, 49–60 (2003).
Singleton, A.B. et al. α-Synuclein locus triplication causes Parkinson's disease. Science 302, 841 (2003).
Singleton, A., Myers, A. & Hardy, J. The law of mass action applied to neurodegenerative disease: a hypothesis concerning the etiology and pathogenesis of complex diseases. Hum. Mol. Genet. 13 (special no 1), R123–R126 (2004).
Conway, K.A., Rochet, J.C., Bieganski, R.M. & Lansbury, P.T., Jr. Kinetic stabilization of the α-synuclein protofibril by a dopamine-α-synuclein adduct. Science 294, 1346–1349 (2001).
Giasson, B.I. et al. Oxidative damage linked to neurodegeneration by selective α-synuclein nitration in synucleinopathy lesions. Science 290, 985–989 (2000).
Iwatsubo, T. et al. Purification and characterization of Lewy bodies from the brains of patients with diffuse Lewy body disease. Am. J. Pathol. 148, 1517–1529 (1996).
Iwatsubo, T. Aggregation of α-synuclein in the pathogenesis of Parkinson's disease. J. Neurol. 250 (suppl. 3), III11–III14 (2003).
Okochi, M. et al. Constitutive phosphorylation of the Parkinson's disease associated α-synuclein. J. Biol. Chem. 275, 390–397 (2000).
Spillantini, M.G. et al. α-synuclein in Lewy bodies. Nature 388, 839–840 (1997).
Emamian, E.S. et al. Serine 776 of ataxin-1 is critical for polyglutamine-induced disease in SCA1 transgenic mice. Neuron 38, 375–387 (2003).
Steffan, J.S. et al. Modification of Huntingtin and Huntington's disease pathology. Science 304, 100–104 (2004).
DiFiglia, M. et al. Aggregation of huntingtin in neuronal intranuclear inclusions and dystrophic neurites in brain. Science 277, 1990–1993 (1997).
Saudou, F., Finkbeiner, S., Devys, D. & Greenberg, M.E. Huntingtin acts in the nucleus to induce apoptosis but death does not correlate with the formation of intranuclear inclusions. Cell 95, 55–66 (1998).
Peters, M.F. et al. Nuclear targeting of mutant Huntingtin increases toxicity. Mol. Cell Neurosci. 14, 121–128 (1999).
de Almeida, L.P., Ross, C.A., Zala, D., Aebischer, P. & Deglon, N. Lentiviral-mediated delivery of mutant huntingtin in the striatum of rats induces a selective neuropathology modulated by polyglutamine repeat size, huntingtin expression levels, and protein length. J. Neurosci. 22, 3473–3483 (2002).
Wellington, C.L. et al. Caspase cleavage of mutant huntingtin precedes neurodegeneration in Huntington's disease. J. Neurosci. 22, 7862–7872 (2002).
Gafni, J. et al. Inhibition of calpain cleavage of Huntingtin reduces toxicity: accumulation of calpain/caspase fragments in the nucleus. J. Biol. Chem. 279, 21211–21220 (2004).
Lunkes, A. et al. Proteases acting on mutant huntingtin generate cleaved products that differentially build up cytoplasmic and nuclear inclusions. Mol. Cell 10, 259–269 (2002).
Poirier, M.A. et al. Huntingtin spheroids and protofibrils as precursors in polyglutamine fibrilization. J. Biol. Chem. 277, 41032–41037 (2002).
Nucifora, F.C., Jr. et al. Nuclear localization of a non-caspase truncation product of atrophin-1, with an expanded polyglutamine repeat, increases cellular toxicity. J. Biol. Chem. 278, 13047–13055 (2003).
Lee, E.N. et al. Phthalocyanine tetrasulfonates affect the amyloid formation and cytotoxicity of α-synuclein. Biochemistry 43, 3704–3715 (2004).
Buxbaum, J.N. Diseases of protein conformation: what do in vitro experiments tell us about in vivo diseases? Trends Biochem. Sci. 28, 585–592 (2003).
Wetzel, R. Ideas of order for amyloid fibril structure. Structure (Camb) 10, 1031–1036 (2002).
Soreghan, B., Kosmoski, J. & Glabe, C. Surfactant properties of Alzheimer's Aβ peptides and the mechanism of amyloid aggregation. J. Biol. Chem. 269, 28551–28554 (1994).
Harper, J.D., Lieber, C.M. & Lansbury, P.T., Jr. Atomic force microscopic imaging of seeded fibril formation and fibril branching by the Alzheimer's disease amyloid-β protein. Chem. Biol. 4, 951–959 (1997).
Lambert, M.P. et al. Diffusible, nonfibrillar ligands derived from Aβ1–42 are potent central nervous system neurotoxins. Proc. Natl. Acad. Sci. USA 95, 6448–6453 (1998).
Harper, J.D., Wong, S.S., Lieber, C.M. & Lansbury, P.T., Jr. Assembly of Aβ amyloid protofibrils: an in vitro model for a possible early event in Alzheimer's disease. Biochemistry 38, 8972–8980 (1999).
Harper, J.D. & Lansbury, P.T., Jr. Models of amyloid seeding in Alzheimer's disease and scrapie: mechanistic truths and physiological consequences of the time-dependent solubility of amyloid proteins. Annu. Rev. Biochem. 66, 385–407 (1997).
Walsh, D.M., Lomakin, A., Benedek, G.B., Condron, M.M. & Teplow, D.B. Amyloid β-protein fibrillogenesis. Detection of a protofibrillar intermediate. J. Biol. Chem. 272, 22364–22372 (1997).
Klein, W.L., Krafft, G.A. & Finch, C.E. Targeting small Aβ oligomers: the solution to an Alzheimer's disease conundrum? Trends Neurosci. 24, 219–224 (2001).
Terry, R.D. et al. Physical basis of cognitive alterations in Alzheimer's disease: synapse loss is the major correlate of cognitive impairment. Ann. Neurol. 30, 572–580 (1991).
McLean, C.A. et al. Soluble pool of Aβ amyloid as a determinant of severity of neurodegeneration in Alzheimer's disease. Ann. Neurol. 46, 860–866 (1999).
Lue, L.F. et al. Soluble amyloid β peptide concentration as a predictor of synaptic change in Alzheimer's disease. Am. J. Pathol. 155, 853–862 (1999).
Walsh, D.M. et al. Naturally secreted oligomers of amyloid β protein potently inhibit hippocampal long-term potentiation in vivo. Nature 416, 535–539 (2002).
Volles, M.J. et al. Vesicle permeabilization by protofibrillar α-synuclein: implications for the pathogenesis and treatment of Parkinson's disease. Biochemistry 40, 7812–7819 (2001).
Sharon, R. et al. The formation of highly soluble oligomers of α-synuclein is regulated by fatty acids and enhanced in Parkinson's disease. Neuron 37, 583–595 (2003).
Chen, S., Berthelier, V., Yang, W. & Wetzel, R. Polyglutamine aggregation behavior in vitro supports a recruitment mechanism of cytotoxicity. J. Mol. Biol. 311, 173–182 (2001).
Sanchez, I., Mahlke, C. & Yuan, J. Pivotal role of oligomerization in expanded polyglutamine neurodegenerative disorders. Nature 421, 373–379 (2003).
Nucifora, F.C., Jr. et al. Interference by huntingtin and atrophin-1 with CBP-mediated transcription leading to cellular toxicity. Science 291, 2423–2428 (2001).
Jiang, H., Nucifora, F.C., Jr., Ross, C.A. & DeFranco, D.B. Cell death triggered by polyglutamine-expanded huntingtin in a neuronal cell line is associated with degradation of CREB-binding protein. Hum. Mol. Genet. 12, 1–12 (2003).
Bence, N.F., Sampat, R.M. & Kopito, R.R. Impairment of the ubiquitin-proteasome system by protein aggregation. Science 292, 1552–1555 (2001).
Kayed, R. et al. Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis. Science 300, 486–489 (2003).
McClellan, A.J. & Frydman, J. Molecular chaperones and the art of recognizing a lost cause. Nat. Cell Biol. 3, E51–E53 (2001).
Goldberg, A.L. Protein degradation and protection against misfolded or damaged proteins. Nature 426, 895–899 (2003).
Ciechanover, A. & Brundin, P. The ubiquitin proteasome system in neurodegenerative diseases: sometimes the chicken, sometimes the egg. Neuron 40, 427–446 (2003).
Kopito, R.R. Aggresomes, inclusion bodies and protein aggregation. Trends Cell Biol. 10, 524–530 (2000).
Ravikumar, B. et al. Inhibitor of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease. Nat. Genet. 36, 585–595 (2004).
Tanaka, M. et al. Aggresomes formed by α-synuclein and synphilin-1 are cytoprotective. J. Biol. Chem. 279, 4625–4631 (2004).
Verhoef, L.G., Lindsten, K., Masucci, M.G. & Dantuma, N.P. Aggregate formation inhibits proteasomal degradation of polyglutamine proteins. Hum. Mol. Genet. 11, 2689–2700 (2002).
Winklhofer, K.F., Reintjes, A., Hoener, M.C., Voellmy, R. & Tatzelt, J. Geldanamycin restores a defective heat shock response in vivo. J. Biol. Chem. 276, 45160–45167 (2001).
Piper, P.W. The Hsp90 chaperone as a promising drug target. Curr. Opin. Investig. Drugs 2, 1606–1610 (2001).
Yamamoto, A., Lucas, J.J. & Hen, R. Reversal of neuropathology and motor dysfunction in a conditional model of Huntington's disease. Cell 101, 57–66 (2000).
Davidson, B.L. & Paulson, H.L. Molecular medicine for the brain: silencing of disease genes with RNA interference. Lancet Neurol. 3, 145–149 (2004).
Miller, V.M. et al. Allele-specific silencing of dominant disease genes. Proc. Natl. Acad. Sci. USA 100, 7195–7200 (2003).
Monsonego, A. & Weiner, H.L. Immunotherapeutic approaches to Alzheimer's disease. Science 302, 834–838 (2003).
Mattson, M.P. & Chan, S.L. Good and bad amyloid antibodies. Science 301, 1847–1849 (2003).
Weiner, H.L. & Selkoe, D.J. Inflammation and therapeutic vaccination in CNS diseases. Nature 420, 879–884 (2002).
Tanaka, M. et al. Trehalose alleviates polyglutamine-mediated pathology in a mouse model of Huntington disease. Nat. Med. 10, 148–154 (2004).
Bohrmann, B. et al. Self-assembly of β-amyloid 42 is retarded by small molecular ligands at the stage of structural intermediates. J. Struct. Biol. 130, 232–246 (2000).
Wood, S.J., MacKenzie, L., Maleeff, B., Hurle, M.R. & Wetzel, R. Selective inhibition of Aβ fibril formation. J. Biol. Chem. 271, 4086–4092 (1996).
Reixach, N., Crooks, E., Ostresh, J.M., Houghten, R.A. & Blondelle, S.E. Inhibition of β-amyloid-induced neurotoxicity by imidazopyridoindoles derived from a synthetic combinatorial library. J. Struct. Biol. 130, 247–258 (2000).
May, B.C. et al. Potent inhibition of scrapie prion replication in cultured cells by bis-acridines. Proc. Natl. Acad. Sci. USA 100, 3416–3421 (2003).
Cordeiro, Y., Lima, L.M., Gomes, M.P., Foguel, D. & Silva, J.L. Modulation of prion protein oligomerization, aggregation, and β-sheet conversion by 4,4'-dianilino-1,1'-binaphthyl-5,5′-sulfonate (bis-ANS). J. Biol. Chem. 279, 5346–5352 (2004).
Heiser, V. et al. Identification of benzothiazoles as potential polyglutamine aggregation inhibitors of Huntington's disease by using an automated filter retardation assay. Proc. Natl. Acad. Sci. USA 99, 16400–16406 (2002).
Pollitt, S.K. et al. A rapid cellular FRET assay of polyglutamine aggregation identifies a novel inhibitor. Neuron 40, 685–694 (2003).
John, V., Beck, J.P., Bienkowski, M.J., Sinha, S. & Heinrikson, R.L. Human β-secretase (BACE) and BACE inhibitors. J. Med. Chem. 46, 4625–4630 (2003).
Petkova, A.T. et al. A structural model for Alzheimer's β-amyloid fibrils based on experimental constraints from solid state NMR. Proc. Natl. Acad. Sci. USA 99, 16742–16747 (2002).
Acknowledgements
Supported by NINDS NS16375, NS38144, NS34172, NS38377, the Huntington's Disease Society of America, the Hereditary Disease Foundation, and the High-Q Foundation. We thank the anonymous reviewers for their comments and suggestions. JCT is supported by NINDS NS16375, NS38377 and NIA AG05146.
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Ross, C., Poirier, M. Protein aggregation and neurodegenerative disease. Nat Med 10 (Suppl 7), S10–S17 (2004). https://doi.org/10.1038/nm1066
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